1. Field of the Invention
The present invention relates to a process for producing purine derivatives which are useful as medicinal agents which have antiviral activity and antitumor activity. More specifically, the present invention relates to a process for producing purine derivatives selectively by a regioselective addition reaction to the 9-position of 7-benzylpurine derivatives, which can easily be obtained from purine nucleosides or derivatives thereof which are easily produced industrially by fermentation.
2. Description of the Background
Nucleoside derivatives which can be selectively incorporated into a viral DNA or RNA and which exhibit the ability to inhibit the replication of viral DNA or RNA are a group of significant compounds which are useful as agents for treating viral infectious diseases such as herpesvirus, herpes zoster, AIDS, hepatitis, cytomegalovirus and the like because of their selective antiviral activity. Especially useful are purine derivatives which have a substituent in the 9-position. These derivatives include a large number of significant known compounds having antiviral activity such as Acyclovir, Ganciclovir, Famciclovir and the like, and other derivatives under development. Known purine derivatives are shown below. ##STR3##
These known purine derivatives are ordinarily synthesized by a method in which a substituent, as a side chain, is added to a purine base. A serious problem of this technique is that it is difficult to introduce a substituent alone at a specific, desired site in the purine base. Many detailed studies have been conducted to solve this problem.
The selectivity for the addition of a substituent at a specific position of the purine base has been studied by a number of investigators. For example, M. Miyaki et al. have reported that when adenine is alkylated, a mixture of substances having substituents in the 3- and 9-positions is obtained (Chem. Pharm. Bull., 18, 1446, 1970). Further, Kjellberg et al have clarified that the selectivity for the 9- or 7-positions upon alkylation varies depending on the difference in the structure between the 1- and 6-positions of guanine derivatives (Nucleosides & Nucleotides, 8, 225, 1989). Still further, Martin et al. have obtained a mixture of substances having substituents in the 9- and 7-positions using diacetylguanine (J. Med. Chem., 26, 759, 1983).
As is apparent from the above-mentioned studies, it is quite difficult to introduce a substituent into the desired position alone of a purine base. When the addition of the substituent occurs in the desired position, but also substitution occurs at another position in the purine base, isomerization has to be conducted after the completion of the addition reaction, or a purification step such as resin treatment or repeated crystallization has to be conducted in order to remove undesired by-product.
For example, when guanine or N-acetylguanine is used as a starting material in the synthesis of the antiviral compound, Penciclovir, the addition of the side chain occurs in two positions, namely, the 9- and 7-positions. Accordingly, an intricate step is required to isolate the intended compound having the substituent in the 9-position, and further the yield thereof is not satisfactory (See Chinese J. of Chem., 9, 536, 1991).
In order to solve this problem, 2-amino-6-chloropurine has been used to improve the selectivity between the 9-position and the 7-position, compared to guanine. However, this method is problematic in that 2-amino-6-chloropurine itself is mutagenic and that the 6-chloro group of the obtained compound has to be hydrolyzed. Further, even if selectivity is improved, it is impossible to completely eliminate the formation of the compound having the side chain in the 7-position. In any case, an intricate purification step is required in this method.
In another study, Graham G. Geen et al. have described the synthesis of Famciclovir by a technique in which an iodo substituted side chain is added to 2-amino-6-chloropurine under basic conditions, thereby obtaining a compound having the side chain in the 9-position (75%) and a compound having the side chain in the 7-position (15%). However, the yield of the compound having the side chain in the 9-position is low, while the yield of the compound having the side chain in the 7-position is relatively high. An intricate treatment step is required to remove the latter compound (Tetrahedron Lett. 46(19), 6903, 1990).
Further, Geen et al have described a Michael-type addition of a side chain precursor to 2-amino-6-chloropurine, as the purine base, to increase the 9-position:7-position ratio to 40:1. However, in this method, the side chain precursor has to be formed for the Michael-type addition. Consequently, the kind of the substituent is limited, which makes it virtually impossible to add the desired side chain as such. Besides, even though the isomer ratio is raised to 40:1, an intricate treatment step is required to completely remove the small amount of isomer having the side chain in the 7-position (Tetrahedron Lett. 33(32) 4609, 1992).
Harden et al. have synthesized Penciclovir by reacting 2-amino-6-chloropurine with a brominated side chain thereby obtaining the desired compound having the side chain in the 9-position in a yield of 70%, and then hydrolyzing this intermediate. However, the selectivity of this synthesis is not described (Tetrahedron Lett. 26(35), 4265, 1985).
Furthermore, Hannah et al. have reacted 2-amino-6-benzyloxypurine with a side chain tosylate to form a compound having a side chain in the 9-position (17%) and a compound having a side chain in the 7-position (8%) (J. Heterocyclic Chem., 26(5), 1261, 1989).
As stated above, the purine derivatives having the substituent in the 9-position have significant potential as medicinal agents. However, as described above, a significant problem in the art is that a mixture of isomers having side chain substitution at both the 9-position and the 7-position is formed. That is, selective substitution only at the 9-position does not occur. Accordingly, a process in which a substituent is selectively introduced only in the 9-position is in demand.
In considering the state of the art, the present inventors believed that since purine derivatives having a benzyl group in the 7-position can be easily formed from natural purine nucleosides or derivatives thereof which are obtained by fermentation, purine derivatives in which a desired substituent is introduced into the 9-position only can be synthesized by introducing the desired substituent into the 9-position of 7-substituted purine derivatives and subsequently removing the substituent in the 7-position.
A method in which 7-benzylguanine is synthesized by reacting guanosine with benzyl bromide, which results in the substitution of the benzyl group in the 7-position of guanosine, and then treating 7-benzylguanine with an acid is known (P. Brookes et al., J. Chem. Soc. (C) 2026, 1968, and P. K. Bridson et al., Synthetic Commun., 20 (16), 2459, 1990). However, the reaction in which a substituent is reintroduced into the 9-position of 7-benzylguanine has not been reported. Further, Brookes et al disclose that 7-benzylxanthine is also synthesized by reacting 7-benzylguanine produced with sodium nitrite in acetic acid.
By the same method, 7-benzylhypoxanthine can also be obtained from inosine (J. Heterocyclic Chem., 25, 1179, 1988). Further, 7-benzyladenine can be synthesized from adenine in three steps (Synthesis 154, 1988). Thus, a purine base in which the 7-position is protected with the benzyl group can be synthesized by a known method.
There are three known ways in which purine base derivatives protected with a benzyl group are alkylated. That is, in 7-benzylxanthine, alkylation occurs in the 3-position under basic conditions (Synthetic Communications, 20, 2459, 1990). In 7-benzylhypoxanthine, an anion is formed with sodium hydride to cause alkylation in the 1-position (J. Heterocyclic Chem., 25, 1179, 1988). In 3-benzyladenine, alkylation occurs in the 7-position under basic conditions (Chem. Pharm. Bull., 34, 2037, 1986).
As described above, purine derivatives having a substituent in the 7-position can be easily formed. However, an addition reaction in which a substituent is selectively introduced into the 9-position of purine derivatives has not yet been reported.
The present inventors have thoroughly conducted investigations to solve the selectivity problem of the art. It has now been found that an addition reaction proceeds selectively at the 9-position by introducing a benzyl group or a substituted benzyl group in the 7-position of natural purine nucleosides, then hydrolyzing the prepared intermediate by the addition of an acid thereby obtaining 7-benzylpurine derivatives, and reacting the obtained 7-benzylpurine derivatives with a desired substituent to achieve 9-position substitution, and then debenzylating the thus-obtained compounds.